Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1

Kleanthi Chalkiadaki, Mehdi Hooshmandi, Gilliard Lach, Elpida Statoulla, Konstanze Simbriger, Ines S Amorim, Stella Kouloulia, Maria Zafeiri, Panagiotis Pothos, Éric Bonneil, Ilse Gantois, Jelena Popic, Sung-Hoon Kim, Calvin Wong, Ruifeng Cao, Noboru H Komiyama, Yaser Atlasi, Seyed Mehdi Jafarnejad, Arkady Khoutorsky, Christos G Gkogkas

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.

Original languageEnglish
Early online date31 Oct 2022
Publication statusE-pub ahead of print - 31 Oct 2022


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